Medicaments having an antiphlogistic action

ABSTRACT

The present invention provides, inter alia, antiphlogistically effective agents, including pharmaceutical compositions containing said agents. Also included are methods for the use of said agents. The active compounds are those of the formula ##STR1## or an ester thereof, in which X denotes a hydrogen atom, an alkyl group, an alkoxy group, an alkylthio group, an alkylsulphinyl or alkylsulphonyl group or a hydroxyl or mercapto group, 
     Y denotes a grouping ##STR2## in which R denotes a hydrogen atom or an alkyl group, and 
     Z denotes a hydroxyl group or an alkoxy or alkylthio group, at least one of the substituents X or Z in each case denoting a sulphur-containing radical.

The present invention relates to the use as antiphlogistic agents ofcertain sulphur-containing organic acids and their esters, some of whichare known.

The use of these sulphur-containing organic acids and esters of thisclass of compounds as medicaments is not known.

According to the present invention there is provided a pharmaceuticalcomposition containing as an active ingredient a compound which is asulphur-containing carboxylic acid of the following general formula##STR3## or an ester thereof, in which X denotes a hydrogen atom, analkyl group, an alkoxy group, an alkylthio group, an alkylsulphinyl oralkylsulphonyl group or a hydroxyl or mercapto group,

Y denotes a grouping ##STR4## in which R denotes a hydrogen atom or analkyl group, and

Z denotes a hydroxyl group or an alkoxy or alkylthio group, at least oneof the substituents X or Z in each case denoting a sulphur-containingradical,

in admixture with a solid or liquefied gaseous diluent or in admixturewith a liquid diluent other than a solvent of molecular weight less than200 except in the presence of a surface-active agent.

Some of the compounds of the general formula (I) claimed as activecompounds for medicaments are known and some are commercially available.

Most of the compounds according to the invention were prepared accordingto the equation which follows, as may be shown using an example:##STR5##

Depending on the concentration of the oxidising agent and depending onthe reaction time used, the individual oxidation stages can be isolated,or mixtures are formed which can be separated by chromatography, as isdescribed in detail in the experimental section.

Those compounds which are in free acid form can, of course, form salts,particularly with alkali and alkaline earth metals, such as sodium,potassium, calcium, etc.

Surprisingly, the sulphur-containing carboxylic acids and estersaccording to the invention exhibit a substantially greater therapeuticrange, coupled with a very good anti-inflammatory action, than thecompounds hitherto known in this field. Furthermore, they have fewerside-effects, such as, for example, heartburn, the formation of ulcers,intestinal haemorrhages and the like. The compounds according to theinvention thus represent an advance in pharmacy.

In detail, examples which may be mentioned of the compounds which can beused according to the invention are: 3-methylsulphinylpropionic acid(CH₃ SOCH₂ CH₂ COOH), S-methyl methacrylthioate (CH₂ ═C(CH₃)COSCH₃).S-methyl crotonylthioate (CH₃ CH═CH--COSCH₃), S-ethyl acrylthioate (CH₂═CH--COSC₂ H₅), S-ethyl 3-ethyl-thiopropionylthioate (C₂ H₅ SCH₂ CH₂COSC₂ H₅), S-methyl 3-methylthio-2-propylcarbonylthioate (CH₃ SCH₂CH(CH₃) COSCH₃), 3-mercaptopropionic acid (HS--CH₂ CH₂ COOH), S-methyl3-methylthiopropionothioate (CH₃ S--CH₂ --CH₂ --COSCH₃), methyl3-methylthiopropionate (CH₃ S--CH₂ --CH₂ --COOCH₃), S-methylacrylthioate (CH₂ ═CH--COSCH₃), methyl 3-mercaptopropionate (HS--CH₂--CH₂ --COOCH₃), 3-methyl thiopropionic acid (CH₃ SCH₂ CH₂ COOH), ethyl3-methylthiopropionate (CH₃ SCH₂ CH₂ COOC₂ H₅), S-propyl3-proplythiopropionothioate (C₃ H₇ SCH₂ CH₂ COSC₃ H₇), S-isopropyl3-isopropylthiopropionothioate (CH₃ CH(CH₃)SCH₂ CH₂ -COSCH(CH₃)CH₃),S-butyl 3-butylthiopropionothioate (C₄ H₉ SCH₂ CH₂ COSC₄ H₉),S-sec.-butyl 3-sec.-butylthiopropionothioate (CH₃ CH₂ CH(CH₃)SCH₂ CH₂COSCH(CH₃)CH₂ CH₃), S-tert.-butyl 3-tert.-butylthiopropionothioate((CH₃)₃ CSCH₂ CH₂ COSC(CH₃)₃), S-isobutyl 3-isobutylthiopropionothioate(CH₃ CH(CH₃)CH₂ SCH₂ CH₂ COSCH₂ CH(CH₃)₂), S-butyl3-butylsulphinylpropionothioate (C₄ H₉ SOCH₂ CH₂ COSC₄ H₉), S-sec.-butyl3-sec.-butylsulphinylpropionothioate (CH₃ CH₂ CH(CH₃)SOCH₂ CH₂COSCH(CH₃)-CH₂ CH₃), S-isopropyl 3-isopropylsulphinylpropionothioate((CH₃)₂ CHSOCH₂ CH₂ COSCH(CH₃)₂), S-propyl3-propylsulphinylpropionothioate (C₃ H₇ SOCH₂ CH₂ COSC₃ H₇), S-ethyl3-ethylsulphinylpropionothioate (C₂ H₅ SOCH₂ COSC₂ H₅), S-tert.-butyl3-tert.-butylsulphinylpropionothioate ((CH₃)₃ CSOCH₂ CH₂ COSC(CH₃)₃),S-ethyl 3-ethylsulphenylpropionothioate (C₂ H₅ SO₂ CH₂ CH₂ COSC₂ H₅),S-sec.-butyl 3-sec.-butylsulphonylpropionothioate (CH₃ CH₂ CH(CH₃)SO₂═CH₂ CH₂ COSCH(CH₃)CH₂ CH₃), 3-tert.-butyl sulphonylpropionic acid((CH₃)₃ CSO₂ CH₂ CH₂ COOH), S-isobutyl3-isobutylsulphonylpropionothioate ((CH₃)₂ CHCH₂ SO₂ CH₂ CH₂ COSCH₂CH(CH₃)₂), S-tert.-butyl 3-tert.-butylsulphonylpropionothioate ((CH₃)₃CSO₂ CH₂ CH₂ COSC(CH₃)₃, 3-sec.-butyl sulphonylpropionic acid (CH₃ CH₂CH(CH₃)SO₂ CH₂ CH₂ COOH), S-butyl 3-butylsulphonylpropionothioate (C₄ H₉SO₂ CH₂ COSC₄ H₉), 3-butyl sulphonylpropionic acid (C₄ H₉ SO₂ CH₂ CH₂COOH), 3-isobutyl sulphonylpropionic acid ((CH₃)₂ CHCH₂ SO₂ CH₂ CH₂COOH), S-isopropyl-3-isopropylsulphonylpropionothioate ((CH.sub. 3)₂CHSO₂ CH₂ CH₂ COSCH(CH₃)₂), S-propyl 3-propylsulphonylpropionothioate(C₃ H₇ SO₂ CH₂ CH₂ COSC₃ H₇) and S-methyl3-methylsulphonylpropionothioate (CH₃ SO₂ CH₂ CH₂ COSCH₃).

The pharmacological action may be demonostrated using S-methyl3-methylthiopropionothioate (designated A in the following text) as anexample.

Substance A possesses a very pronounced antiphlogistic action and isoutstandingly suitable for parenteral use. The anti-inflammatory actionwas detected in paw oedemas, caused by the administration of kaolin, inrates. The ED₅₀ value was 4.85 μmols/kg after intramuscular injection.This value clearly shows, also in comparison with the ED₅₀ values,determined by the same method, for known commercially availableantiphlogistic agents (see Table 1), that compound A greatly inhibitsexperimental inflammation.

It is known that almost all non-steroidal antiphlogistic agents lead todamage to the mucous membrane of the gastrointestinal tract inwarm-blooded animals. Tests were therefore carried out to discoverwhether compound A has an ulcerogenic action after intramuscular use.

A ED₅₀ of 256.41 μmols/kg was found in rats. From the difference in dosebetween the two ED₅₀ values it can be seen that, measured by these twocriteria, compound A has a wide therapeutic range.

Furthermore, A also has an action on other inflammation models. The ED₅₀values which follow are found (mg/kg; intramuscularly): formalin oedema5.4, albumiun oedema 6.3, yeast oedema 27.4, concanavalin oedema 3.4 andtrypsin oedema 2.0.

These comments can be further reinforced by the determination of theacute toxicity of compound A in rats after intramuscular injection.

The LD₅₀ was 4,587 μmols/kg.

The large difference between this value and the ED₅₀ value for thekaolin oedema underlines the unexpected favourable therapeutic range forcompound A. The above results are compared with the corresponding valuesfor flufenamic acid, phenylbutazone and indometacin in the table. Theprominant position of compound A in respect of its therapeutic range canbe seen by comparing the figures in the last two columns of the table.

                                      TABLE 1                                     __________________________________________________________________________    Comparison of the therapeutic range                                           Rats                                                                                                             Therapeutic range                           Substance                                                                           ED.sub.50 μmols/kgKaolin oedema                                                    ED.sub.50 μmols/kgStomach ulcer                                                    μmols/kgLD.sub.50                                                                 strationadmini-Method of                                                            ##STR6##                                  __________________________________________________________________________    S-methyl 3-                                                                   methylthio-                                                                             5.76*   429.18 4,950                                                                             intra-                                           propiono-                                                                           4.85    256.41  4,587  muscular                                                                            52.86   945.77                             thioate   3.38    172.41 4,255                                                Flufenamic                                                                              50.9    78.7   3.065                                                acid  36.2    55.1    2,037  oral  1.52    56.27                                        23.9    32.7   1,632                                                Phenyl-   167.4   234.9  4,803                                                butazone                                                                            122     181.6   3,217  oral  1.48    26.36                                        92.8    145.0  2,317                                                Indo-     3.9     21.0   85                                                   metacin                                                                             2.9     11.1    68     oral  3.81    23.44                                        2.3     6.4    55                                                   __________________________________________________________________________     *The data denote confidence ranges with a probable error of 5%.          

In addition to the effects described for compound A, it could also beshown that the other derivatives (see Table 2) likewise have a powerfulanti-inflammatory action. The minimum doses which still cause a clearlydetectable effect on the paw oedema after the administration of kaolinare listed in Table 2.

                                      TABLE 2                                     __________________________________________________________________________    Antiphlogistic action                                                         Rats, kaolin oedema, intramuscularly, n = 10/dose group                                                       Inhibition in %                                                           Dose                                                                              of the controls                               Compound                    mg/kg                                                                             ED.sub.50 in mg/kg                            __________________________________________________________________________    HSCH.sub.2 CH.sub.2 COOH    20.00                                                                             8.5                                           C.sub.2 H.sub.5 SCH.sub.2 CH.sub.2 COSC.sub.2 H.sub.5                                                     2.50                                                                              58.2 (3.75)                                   CH.sub.3 CH═CHCOSCH.sub.3                                                                             12.50                                                                             16.0                                          CH.sub.2 ═C(CH.sub.3)COSCH.sub.3                                                                      5.00                                                                              21.8                                          CH.sub.3 SOCH.sub.2 CH.sub.2 COSCH.sub.3                                                                  3.12                                                                              10.2 (1.8)                                    CH.sub.3 SCH.sub.2 CH(CH.sub.3)COSCH.sub.3                                                                0.65                                                                              16.6 (4.5)                                    CH.sub.2 ═CHCOSC.sub.2 H.sub.5                                                                        0.32                                                                              18.5 (1.5)                                    CH.sub.3 SCH.sub.2 CH.sub.2 COOC.sub.2 H.sub.5                                                            25  16                                            (CH.sub.3).sub.3 CSCH.sub.2 CH.sub.2 COSC(CH.sub.3).sub.3                                                 12.5                                                                              23.3                                          (CH.sub.3).sub.2 CHSCH.sub.2 CH.sub.2 COSCH(CH.sub.3).sub.2                                               25  63.2                                          C.sub.3 H.sub.7 SCH.sub.2 CH.sub.2 COSC.sub.3 H.sub.7                                                     25  68.5                                          C.sub.4 H.sub.9 SCH.sub.2 CH.sub.2 COSC.sub.4 H.sub.9                                                     50  77.2                                          CH.sub.3 CH.sub.2 CH(CH.sub.3)SCH.sub.2 CH.sub.2 COSCH(CH.sub.3)CH.sub.2      CH.sub.3                    50  72                                            (CH.sub.3 ).sub.2 CHCH.sub.2 SCH.sub.2 CH.sub.2 COSCH.sub.2 CH(CH.sub.3).s    ub.2                        50  77.2                                          (CH.sub.3).sub.2 CHSOCH.sub.2 CH.sub.2 COSCH(CH.sub.3).sub.2                                              12.5                                                                              22.7                                          (CH.sub.3).sub.2 CHCH.sub.2 SOCH.sub.2 CH.sub.2 COSCH.sub.2 CH(CH.sub.3).s    ub.2                        12.5                                                                              17.9                                          CH.sub.3 CH.sub.2 CH(CH.sub.3)SO.sub.2 CH.sub.2 CH.sub.2 COSCH(CH.sub.3)CH    .sub.2 CH.sub.3             12.5                                                                              33                                            (CH.sub.3).sub.2 CHCH.sub.2 SO.sub.2 CH.sub.2 CH.sub.2 COSCH.sub.2            CH(CH.sub.3).sub.2          12.5                                                                              42                                            C.sub.3 H.sub.7 SOCH.sub.2 CH.sub.2 COSC.sub.3 H.sub.7                                                    100 73                                            CH.sub.3 CH.sub.2 CH(CH.sub.3)SOCH.sub.2 CH.sub.2 COSCH(CH.sub.3)CH.sub.2     CH.sub.3                    100 90.5                                          C.sub.4 H.sub.9 SOCH.sub.2 CH.sub.2 COSC.sub.4 H.sub.9                                                    100 73                                            __________________________________________________________________________

The use of compounds of the general formula (I) in which

X represents hydrogen, alkyl, alkoxy, alkylthio, alkylsulphinyl,alkylsulphonyl or a mercapto group, the abovementioned alkyl and alkoxygroups in each case containing 1 to 4 carbon atoms;

Y represents the grouping ##STR7## wherein R denotes hydrogen or alkylwith 1 to 4 carbon atoms, and

Z represents hydroxyl, alkoxy or alkylthio with in each case 1 to 4carbon atoms in the alkoxy and alkyl radical,

is of particular interest.

As stated above, the invention also relates to the use in medicine ofthe compounds of the invention.

The present invention provides a pharmaceutical composition containingas active ingredient a compound of the invention in admixture with asolid or liquefied gaseous diluent, or in admixture with a liquiddiluent other than a solvent of a molecular weight less than 200(preferably less than 350) except in the presence of a surface activeagent.

The invention further provides a pharmaceutical composition containingas active ingredient a compound of the invention in the form of asterile and/or physiologically isotonic aqueous solution.

The invention also provides a medicament in dosage unit form comprisinga compound of the invention.

The invention also provides a medicament in the form of tablets(including lozenges and granules), dragees, capsules, pills, ampoules orsuppositories comprising a compound of the invention.

"Medicament" as used in this specification means physically discretecoherent portions suitable for medical administration. "Medicament indosage unit form" as used in this Specification means physicallydiscrete coherent units suitable for medical administration eachcontaining a daily dose or a multiple (up to four times) or submultiple(down to a fortieth) of a daily dose of the compound of the invention inassociation with a carrier and/or enclosed within an envelope. Whetherthe medicament contains a daily dose or, for example, a half, a third ora quarter of a daily dose will depend on whether the medicament is to beadministered once or, for example, twice, three times or four times aday respectively.

The pharmaceutical compositions according to the invention may, forexample, take the form of ointments, gels, pastes, creams, sprays(including aerosols), lotions, suspensions, solutions and emulsions ofthe active ingredient in aqueous or non-aqueous diluents, syrups,granulates or powders.

The diluents to be used in pharmaceutical compositions (e.g. granulates)adapted to be formed into tablets, dragees, capsules and pills includethe following: (a) fillers and extenders, e.g. starch, sugars, mannitol,and silicic acid; (b) binding agents, e.g. carboxymethyl cellulose andother cellulose derivatives, alginates, gelatine and polyvinylpyrrolidone; (c) moisturizing agents, e.g. glycerol; (d) disintegratingagents, e.g. agar-agar, calcium carbonate and sodium bicarbonate; (e)agents for retarding dissolution e.g. paraffin; (f) resorptionaccelerators, e.g. quaternary ammonium compounds; (g) surface activeagents, e.g. cetyl alcohol, glycerol monostearate; (h) absorptivecarriers, e.g. kaolin and bentonite; (i) lubricants, e.g. talc, calciumand magnesium stearate and solid polyethyl glycols.

The tablets, dragees, capsules and pills formed from the pharmaceuticalcompositions of the invention can have the customary coatings, envelopesand protective matrices, which may contain opactifiers. They can be soconstituted that they release the active ingredient only or preferablyin a particular part of the intestinal tract, possibly over a period oftime. The coatings, envelopes and protective matrices may be made, forexample, of polymeric substances or waxes.

The ingredient can also be made up in microencapsulated form togetherwith one or several of the above-mentioned diluents.

The diluents to be used in pharmaceutical compositions adapted to beformed into suppositories can, for example, be the usual water-solublediluents, such as polyethylene glycols and fats (e.g. cocoa oil and highesters [e.g. C₁₄ -alcohol with C₁₆ -fatty acid]) or mixtures of thesediluents.

The pharmaceutical compositions which are ointments, pastes, creams andgels can, for example, contain the usual diluents, e.g. animal andvegetable fats, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide or mixtures of these substances.

The pharmaceutical compositions which are powders and sprays can, forexample, contain the usual diluents, e.g. lactose, talc, silicic acid,aluminium hydroxide, calcium silicate, and polyamide powder or mixturesof these substances. Aerosol sprays can, for example, contain the usualpropellants, e.g. chlorofluorohydrocarbons.

The pharmaceutical compositions which are solutions and emulsions can,for example, contain the customary diluents (with, of course, theabove-mentioned exclusion of solvents having a molecular weight below200 except in the presence of a surface-active agent), such as solvents,dissolving agents and emulsifiers; specific examples of such diluentsare water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils[for example ground nut oil], glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitol or mixtures thereof.

For parenteral administration, solutions and emulsions should besterile, and, if appropriate, blood-isotonic.

The pharmaceutical compositions which are suspensions can contain theusual diluents, such as liquid diluents, e.g. water, ethyl alcohol,propylene glycol, surface-active agents (e.g. ethoxylated isostearylalcohols, polyoxyethylene sorbite and sorbitane esters),micro-crystalline cellulose, aluminium metahydroxide, bentonite,agar-agar and tragacanth or mixtures thereof.

All the pharmaceutical compositions according to the invention can alsocontain colouring agents and preservatives as well as perfumes andflavouring additions (e.g. peppermint oil and eucalyptus oil) andsweetening agents (e.g. saccharin).

The pharmaceutical compositions according to the invention generallycontain from 0.1 to 99.5, usually from 0.5 to 95% of the activeingredient by weight of the total composition.

In addition to a compound of the invention, the pharmaceuticalcompositions and medicaments according to the invention can also containother pharmaceutically active compounds. They may also contain aplurality of compounds of the invention.

Any diluent in the medicaments of the present invention may be any ofthose mentioned above in relation to the pharmaceutical compositions ofthe present invention. Such medicaments may include solvents ofmolecular weight less than 200 as sole diluent.

The discrete coherent portions constituting the medicament according tothe invention will generally be adapted by virtue of their shape orpackaging for medical administration and may be, for example, any of thefollowing: tablets (including lozenges and granulates), pills, dragees,capsules, suppositories and ampoules. Some of these forms may be made upfor delayed release of the active ingredient. Some, such as capsules,include a protective envelope which renders the portions of themedicament physically discrete and coherent.

The preferred daily dose for administration of the medicaments of theinvention is 20 to 800, preferably 100 to 500, mg of active ingredient.An individual administration preferably contains the active compound orcompounds in amounts of 10 to 30, preferably 50 to 200, mg/dose.

The product of the above-mentioned pharmaceutical compositions andmedicaments is carried out by any method known in the art, for example,by mixing the active ingredient(s) with the diluent(s) to form apharmaceutical composition (e.g. a granulate) and then forming thecomposition into the medicament (e.g. tablets).

This invention further provides a method of combating (includingprevention, relief and cure of) the above-mentioned diseases inwarm-blooded animals, which comprises administering to the animals acompound of the invention alone or in admixture with a diluent or in theform of a medicament according to the invention.

It is envisaged that these active compounds will be administeredperorally, parenterally (for example intramuscularly, intraperitoneally,subcutaneously and intravenously), rectally or locally, preferablyparenterally. Preferred pharmaceutical compositions and medicaments aretherefore those adapted for administration such as parenteraladministration. Administration in the method of the invention ispreferably parenteral administration.

In general it has proved advantageous to administer amounts of from 0.4mg to 16 mg/kg, preferably 2 mg to 10 mg/kg, of body weight per day toachieve effective results. Nevertheless, it can at times be necessary todeviate from those dosage rates, and in particular to do so as afunction of the nature and body weight of the subject to be treated, theindividual reaction of this subject to the treatment, the type offormulation in which the active ingredient is administered and the modein which the administration is carried out, and the point in theprogress of the disease or interval at which it is to be administered.Thus it may in some cases suffice to use less than the above-mentionedminimum dosage rate, whilst other cases the upper limit mentioned mustbe exceeded to achieve the desired results. Where larger amounts areadministered it can be advisable to divide these into several individualadministrations over the course of the day.

The following Examples illustrate the preparation of compounds offormula (I).

EXAMPLE 1 S-Methyl 3-methylsulphinylpropionothioate CH₃ SO--CH₂ --CH₂--COSCH₃

3 g (0.02 mol) of S-methyl 3-methylthiopropionothioate are dissolved ina mixture of 200 ml of water and 160 ml of acetone, 3 drops of glacialacetic acid are added, 2.83 ml of 30% strength hydrogen peroxidesolution are added dropwise in the course of 51/2 hours and the mixtureis kept overnight. The reaction solution is then evaporated in vacuo andthe oily residue is kept at 5° C. for seven days. The partiallycrystalline sludge is taken up in ethyl acetate and chromatographed onsilica gel. 0.75 g (22.6% of theory) of S-methyl3-methylsulphinylpropionothioate is thus obtained as an oil.

C₅ H₁₀ O₂ S₂ (166.3): Calculated: C 36.12%, H 6.06%, S 38.57%; Found: C36.06%, H 5.99%, S 38.54%.

EXAMPLE 2 S-Methyl 3-methylsulphonylpropionothioate CH₃ SO₂ CH₂ CH₂COSCH₃

The compound is obtained as the more rapidly migrating fraction in thechromatography in Example 1. Melting point 72° to 73° C.; yield: 0.5 g(13% of theory).

C₅ H₁₀ O₃ S₂ (182.267): Calculated: C 32.95%, H 5.53%, S 35.18%; Found:C 32.99%, H 5.51%, S 35.18%.

EXAMPLE 3 S-Methyl 3-methoxypropionothioate CH₃ OCH₂ --CH₂ COSCH₃

A solution of 41.2 g (0.2 mol) of dicyclohexylcarbodiimide in 40 ml ofmethylene chloride is added to a solution of 20.8 g (0.2 mol) of3-methoxypropionic acid in 60 ml of methylene chloride and after themixture has been cooled to -10° C., 12 ml (0.22 mol) of methanethiol(precooled with acetone/CO₂) are added. After leaving the mixture tostand at room temperature for 15 hours, excess dicyclohexylcarbodiimideis destroyed by adding 2 ml of 50% strength acetic acid, the reactionsolution is stirred and shortly afterwards the urea which hasprecipitated is filtered off. The filtrate is washed with water, driedand distilled in vacuo.

9.1 g (34% of theory) of S-methyl 3-methoxypropionothioate are obtainedas a yellowish oil of boiling point₁₂₋₁₃ 65° to 70° C.

C₅ H₁₀ O₂ S (134.201): Calculated: C 44.75%, H 7.51%, S 23.89%; Found: C44.87%, H 7.46%, S 23.73%.

EXAMPLE 4 Ethyl 3-methylthiopropionate CH₃ SCH₂ CH₂ COCH₂ CH₃

A mixture of 20 g (0.2 mol) of ethyl acrylate in 100 ccs (0.25 mol) oftetrahydrofurane and 2.35 g (21 mmols) of potassium tert.-butylate iskept in a laboratory autoclave at room temperature for 8 days and thenat 50° C. for 4 hours. The reaction mixture is filtered, the filtrate isevaporated in vacuo and the highly mobile oil which remains isdistilled.

Boiling point₁₂ 84°-86° C.; yield: 24.1 g (81.5% of theory).

(Literature boiling point₁₈ 88° C.)

GENERAL PREPARATION INSTRUCTIONS FOR S-ALKYL 3-ALKYLTHIOPROPIONOTHIOATESEXAMPLE 5 S-Methyl 3-methylthiopropionothioate CH₃ SCH₂ CH₂ COSCH₃

A solution of 8 g (0.2 mol) of NaOH in 160 ccs of water is cooled to-10° C., a 25 ccs ampoule (0.466 mol) of methylmercaptan, cooled inacetone/dry ice, is added and 18.1 g=15.8 ccs (0.2 mol) of acryloylchloride are then added in portions. After the final addition, themixture is stirred at room temperature for 2 hours and is then left tostand overnight.

The oil which has separated out is separated off, the aqueous phase isextracted by shaking with ether and the oil phase and ether phase arecombined, dried over Na₂ SO₄ and fractionated.

Boiling point₂₀ 114°-117° C.; yield: 24.3 g (81% of theory), slightlyyellowish oil.

C₅ H₁₀ OS₂ (150.267): Calculated: C 39.97%, H 6.71%, S 42.68%; Found: C40.20%, H 6.63%, S 42.50%.

The following compounds are prepared in a similar manner:

EXAMPLE 6 S-Ethyl 3-ethylthiopropionothioate C₂ H₅ SCH₂ CH₂ COSC₂ H₅

Boiling point₅₅ 157°-160° C.; yield: 67.4% of theory.

C₇ H₁₄ OS₂ (178.3): Calculated: C 47.15%, H 7.91%, S 35.96%; Found: C47.30%, H 7.85%, S 35.91%.

EXAMPLE 7 S-Propyl 3-propylthiopropionothioate C₃ H₇ SCH₂ CH₂ COSC₃ H₇

Boiling point₀.08 78°-80° C.; yield: 78% of theory.

C₉ H₁₈ OS₂ (206.4): Calculated: C 52.38%, H 8.79%, S 31.08%; Found: C52.47%, H 8.83%, S 30.97%.

EXAMPLE 8 S-Isopropyl 3-isopropylthiopropionothioate (CH₃)₂ CHSCH₂ CH₂COSC(CH₃)₂

Boiling point₀.15 82°-83° C.; yield: 70% of theory.

C₉ H₁₈ OS₂ (206.4): Calculated: C 52.38%, H 8.79%, S 31.08%; Found: C52.36%, H 8.66%, S 30.95%.

EXAMPLE 9 S-Butyl 3-butylthiopropionothioate C₄ H₉ SCH₂ CH₂ COSC₄ H₉

Boiling point₀.15 95°-102° C.; yield: 80% of theory.

C₁₁ H₂₂ OS₂ (234.4): Calculated: C 56.36%, H 9.46%, S 27.36%; Found: C56.40%, H 9.44%, S 27.48%.

EXAMPLE 10 S-sec.-Butyl 3-sec.-butylthiopropionothioate CH₃ CH₂CH(CH₃)SCH₂ CH₂ COSCH(CH₃)CH₂ CH₃

Boiling point₀.2 101°-105° C.; yield: 69% of theory.

C₁₁ H₂₂ OS₂ (234.4): Calculated: C 56.36%, H 9.46%, S 27.36%; Found: C56.30%, H 9.46%, S 27.35%.

EXAMPLE 11 S-tert.-Butyl 3-tert.-butylthiopropionothioate (CH₃)₃ CSCH₂CH₂ COSC(CH₃)₃

Boiling point₂₈ 160°-162° C. (literature boiling point₁₁ 135°-136°);yield: 50% of theory.

C₁₁ H₂₂ OS₂ (234.4): Calculated: C 56.36%, H 9.46%, S 27.36%; Found: C56.48%, H 9.35%, S 27.14%.

EXAMPLE 12 S-Isobutyl 3-isobutylthiopropionothioate CH₃ CH(CH₃)CH₂ SCH₂CH₂ COSCH₂ CH(CH₃)CH₃

Boiling point₀.2 107°-110° C.; yield: 64% of theory.

C₁₁ H₂₂ OS₂ (234.4): Calculated: C 56.36%, H 9.46%, S 27.36%; Found: C56.30%, H 9.41%, S 27.40%.

Oxidation of the above S-alkyl 3-alkylthiopropionothioates

Method A: in glacial acetic acid, with 1 mol of hydrogen peroxide.

EXAMPLE 13 S-Butyl 3-butylsulphinylpropionothioate C₄ H₉ SOCH₂ CH₂CO--SC₄ H₉

9.37 g (40 mols) of S-butyl 3-butylthiopropionothioate are dissolved in9 ccs of glacial acetic acid and 4 ccs (40 mmols) of 30% strengthhydrogen peroxide are added dropwise, whilst stirring and cooling in anice bath. After warming the mixture to room temperature, it is allowedto react for 2 hours and then diluted with water and the product issubsequently extracted with methylene chloride. After evaporating offthe solvent in vacuo, the residue is chromatographed on silica gel.Small amounts of S-butyl 3-butylthiopropionothioate and S-butyl3-butylsulphonylpropionothioate are separated off by washing with ether.Subsequent elution with methylene chloride and evaporating off thesolvent from the eluate in vacuo gives 5.75 g (57.5% of theory) of oilyS-butyl 3-butylsulphinylpropionothioate.

C₁₁ H₂₂ O₂ S₂ (250.4): Calculated: C 52.76%, H 8.85%, S 25.61%; Found: C52.99%, H 8.48%, S 24.32%.

The following compounds are prepared in a similar manner:

EXAMPLE 14 S-sec.-Butyl 3-sec.-butylsulphinylpropionothioate CH₃ CH₂CH(CH₃)SOCH₂ CH₂ COSCH(CH₃)CH₂ CH₃

Yield: 89% of theory; oil.

C₁₁ H₂₂ O₂ S₂ (250.4): Calculated: C 52.76%, H 8.85%, S 25.61%; Found: C52.84%, H 8.89%, S 25.63%.

EXAMPLE 15 S-Isopropyl 3-isopropylsulphinylpropionothioate (CH₃)₂CHSOCH₂ CH₂ COSCH(CH₃)₂

Yield: 62.5% of theory; oil.

C₉ H₁₈ O₂ S₂ (222.4): Calculated: C 48.61%, H 8.16%, S 28.84%; Found: C48.84%, H 8.00%, S 28.84%.

EXAMPLE 16 S-Propyl 3-propylsulphinylpropionothioate C₃ H₇ SOCH₂ CH₂COSC₃ H₇

Yield: 56.3% of theory; oil.

C₉ H₁₈ O₂ S₂ (222.4): Calculated: C 48.61%, H 8.16%, S 28.84%; Found: C48.58%, H 8.26%, S 28.75%.

EXAMPLE 17 S-Ethyl 3-ethylsulphinylpropionothioate C₂ H₅ SOCH₂ CH₂ COSC₂H₅

Melting point 35.5°-36° C.; yield: 55.4% of theory.

C₇ H₁₄ O₂ S₂ (194.3): Calculated: C 43.27%, H 7.26%, S 33.00%; Found: C43.15%, H 7.30%, S 32.97%.

EXAMPLE 18 S-tert.-Butyl 3-tert.-butylsulphinylpropionothioate (CH₃)₃CSOCH₂ CH₂ COSC(CH₃)₃

Melting point 72.5°-73.5° C.; yield: 61.9% of theory.

C₁₁ H₂₂ O₂ S₂ (250.4): Calculated: C 5276%, H 8.85%, S 25.61%; Found: C52.85%, H 8.70%, S 25.51%.

Method B: in glacial acetic acid, with 2 mols of hydrogen peroxide,reaction time 3-4 days.

EXAMPLE 19 S-Ethyl 3-ethylsulphinylpropionothioate and S-ethyl3-ethylsulphonylpropionothioate C₂ H₅ SO₂ CH₂ CH₂ COSC₂ H₅

7.13 g (40 mmols) of S-ethyl 3-ethylthiopropionothioate are dissolved in5 ccs of glacial acetic acid, and 8 ccs (80 mmols) of 30% strengthhydrogen peroxide are added dropwise, whilst stirring and cooling in anice bath. The reaction solution is left to react at room temperature forthree days, diluted with water and extracted with methylene chloride andthe oil which remains after evaporating off the solvent ischromatographed on silica gel.

Elution with ether gives 1.5 g (17.8% of theory) of S-ethyl3-ethylsulphonyl-propionothioate of melting point 35°-36° C.

C₇ H₁₄ O₃ S₂ (210,32): Calculated: C 39.98%, H 6.71%, S 30.49%; Found: C40.17%, H 6.71%, S 30.40%.

2.8 g (36.1% of theory) of S-ethyl 3-ethylsulphinylpropionothioate ofmelting point 35.5°-36° C. are obtained by subsequent elution withacetone.

The following compounds are prepared in a similar manner:

EXAMPLE 20 S-sec.-Butyl 3-sec.-butylsulphonylpropionothioate

CH₃ CH₂ CH(CH₃)SO₂ CH₂ CH₂ COCH(CH₃)CH₂ CH₃ is obtained fromS-sec.-butyl 3-sec.-butylthiopropionothioate.

Yield: 31.1% of theory; oil.

C₁₁ H₂₂ O₃ S₂ (266.4): Calculated: C 49.59%, H 8.32%, S 24.07%; Found: C50.35%, H 8.29%, S 23.71%.

In addition: S-sec.-butyl 3-sec.-butylsulphinylpropionothioate

Yield: 30% of theory.

EXAMPLE 21 S-Isobutyl 3-isobutylsulphonylpropionothioate (CH₃)₂ CHCH₂SO₂ CH₂ CH₂ COSCH₂ CH(CH₃)₂ is obtained from S-isobutyl3-isobutylthiopropionothioate.

Melting point 43°-44° C.; yield: 20% of theory.

C₁₁ H₂₂ O₃ S₂ (266.4): Calculated: C 49.59%, H 8.32%, S 24.07%; Found: C49.70%, H 8.29%, S 24.01%.

In addition: S-isobutyl 3-isobutylsulphinylpropionothioate

Yield: 30% of theory; waxy substance.

C₁₁ H₂₂ O₂ S₂ (250.4): Calculated: C 52.76%, H 8.85%, S 25.61%; Found: C52.94%, H 8.91%, S 25.68%.

EXAMPLE 22 S-tert.-Butyl 3-tert.-butylsulphonylpropionothioate

(CH₃)₃ CSO₂ CH₂ CH₂ COSC(CH₃)₃ is obtained from tert.-butyl3-tert.-butylthiopropionothioate.

Melting point 98°-99° C.; yield: 22.6% of theory.

C₁₁ H₂₂ O₃ S₂ (266.4): Calculated: C 49.59%, H 8.32%, S 24.07%; Found: C49.47%, H 8.18%, S 24.24%.

In addition: S-tert.-butyl 3-tert.-butylsulphinylpropionothioate

Melting point 73°-74° C.; yield: 34% of theory.

If the mixture is not cooled during the dropwise addition of hydrogenperoxide, only 3-tert.-butylsulphonylpropionic acid is formed, in anexothermic reaction.

(CH₃)₃ CSO₂ CH₂ CH₂ COOH:

Melting point 103° C.; yield: 14.2% of theory.

C₇ H₁₄ O₃ S (194.3): Calculated: C 43.28%, H 7.26%, S 16.51%; Found: C43.57%, H 7.33%, S 16.61%.

Method C: in glacial acetic acid, with 2 mols of hydrogen peroxide;reaction time 10-14 days.

EXAMPLE 23 S-sec.-Butyl 3-sec.-butylsulphonylpropionothioate andS-sec.-Butylsulphonylpropionic acid CH₃ CH₂ CH(CH₃)SO₂ CH₂ CH₂ COOH

9.37 g (40 mmols) of S-sec.-butyl 3-sec.-butylthiopropionothioate aredissolved in 17 ccs of glacial acetic acid, and 8 ccs (˜80 mmols) of 30%strength hydrogen peroxide are added dropwise, whilst stirring andcooling in an ice bath. The mixture is allowed to react at roomtemperature for 14 days and diluted with water, the reaction mixture isextracted with methylene chloride and the oily evaporation residue ofthe extract is chromatographed on silica gel.

2.35 g (22.2% of theory) of S-sec.-butyl3-sec-butylsulphonylpropionothioate are obtained by elution withdiisopropyl ether.

Subsequent washing of the column with acetone gives 2 g (25.8% oftheory) of 3-sec.-butylsulphonylpropionic acid of melting point 66°-67°C.

C₇ H₁₄ O₄ S (194.3): Calculated: C 43.28%, H 7.26%, S 16.61%; Found: C43.22%, H 7.15%, S 16.66%.

The following compounds are prepared in a similar manner:

EXAMPLE 24

S-Butyl 3-butylsulphonylpropionothioate is obtained from S-butyl3-butylthiopropionothioate.

Melting point 46°-47° C.; yield: 10.4% of theory.

C₁₁ H₂₂ O₃ S₂ (266.4): Calculated: C 49.59%, H 8.32%, S 24.07%; Found: C49.82%, H 8.38%, S 23.87%.

In addition: 3-butylsulphonylpropionic acid.

C₄ H₉ SO₂ CH₂ CH₂ COOH:

Melting point 111°-111.5° C.; yield: 24.5% of theory.

C₇ H₁₄ O₄ S (194.3): Calculated: C 43.28%, H 7.26%, S 16.61%; Found: C43.34%, H 7.31%, S 16.48%.

EXAMPLE 25

S-Isobutyl 3-isobutylsulphonylpropionothioate is obtained fromS-isobutyl 3-isobutylthiopropionothioate.

Melting point 42°-43° C; yield: 6.1% of theory.

In addition: 3-isobutylsulphonylpropionic acid.

Melting point 106°-107° C.; yield: 11.6% of theory.

C₇ H₁₄ O₄ S (194.3): Calculated: C 43.28%, H 7.26%, S 16.51%; Found: C43.43%. H 7.25%, S 16.48%.

Method D: in aqueous acetone, with 2 mols of hydrogen peroxide.

EXAMPLE 26 S-Isopropyl 3-isopropylsulphonylpropionothioate (CH₃)₂ CHSO₂CH₂ CH₂ COSCH(CH₃)₂ and S-isopropyl 3-isopropylsulphinylpropionothioate

4.12 g (20 mmols) of S-isopropyl 3-isopropylthiopropionothioate aredissolved in a mixture of 20 ccs of water and 60 ccs of acetone andafter the solution has been cooled to 0° C., a few drops of glacialacetic acid are added and 4 ccs (40 mmols) of 30% strength hydrogenperoxide are added dropwise, whilst stirring. The reaction mixture iskept at room temperature for 8 days, treated with a spatula tip ofplatinum black in order to destroy excess hydrogen peroxide andfiltered, the filtrate is evaporated in vacuo and the residue ischromatographed on silica gel.

1.9 g (39.9% of theory) of S-isopropyl3-isopropylsulphonylpropionothioate of melting point 45°-47° C. areobtained by elution with ether.

C₉ H₁₈ O₃ S₂ (238.4): Calculated: C 45.34%, H 7.62%, S 26.90%; Found: C45.53%, H 7.56%, S 26.80%.

Subsequent elution with acetone gives 1.2 g (27% of theory) of oilyS-isopropyl 3-isopropylsulphinylpropionothioate.

The following compound is prepared in a similar manner:

EXAMPLE 27 S-Propyl 3-propylsulphonylpropionothioate

C₃ H₇ SO₂ CH₂ CH₂ COSC₃ H₇ is obtained from S-propyl3-propylthiopropionothioate. Melting point 55°-56° C.; yield: 18.5% oftheory.

C₈ H₁₈ O₃ S₂ (238.4): Calculated: C 45.34%, H 7.62%, S 26.90%; Found: C45.63%, H 7.59%, S 26.91%.

What is claimed is:
 1. A pharmaceutical composition containing as anactive ingredient, an antiphlogistically effective amount of asulphur-containing carboxylic acid of the formula ##STR8## or its ester,in which X denotes a hydrogen atom, an alkyl group, an alkoxy group, analkylthio group, an alkylsulphinyl or alkylsulphonyl group or a hydroxylor mercapto group,Y denotes a grouping ##STR9## in which R denotes ahydrogen atom or an alkyl group, and Z denotes an alkylthio group, andeach of said alkyl, alkoxy or alkylthio moiety containing up to 8 carbonatoms, in the form of a sterile or physiologically isotonic aqueoussolution, tablets, pills, dragees, capsules, ampoules or suppositories.2. A composition according to claim 1, in which the active ingredient isa compound as defined in claim 1 in which X denotes a hydrogen atom oran alkyl, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl or amercapto group, the alkyl and alkoxy groups in each case containing 1 to4 carbon atoms, Y denotes a grouping ##STR10## in which R denotes ahydrogen atom or an alkyl group with 1 to 4 carbon atoms, and Z denotesan alkylthio group with 1 to 4 carbon atoms.
 3. A composition accordingto claim 1 in which the active ingredient is S-methyl3-methylthiopropionothioate.
 4. A pharmaceutical composition containingas an active ingredient an antiphlogistically effective amount of acompound as defined in claim 1 in the form of a sterile orphysiologically isotonic aqueous solution.
 5. A pharmaceuticalcomposition of claim 4 wherein the active compound is S-methyl3-methylthiopropionothionate.
 6. A composition according to claim 1containing from 0.5 to 95% of the said active ingredient, by weight. 7.A composition of claim 1 in the form of tablets, pills, dragees,capsules, ampoules, or suppositories.
 8. A pharmaceutical compositionaccording to claim 1 containing as an active ingredient a compound whichis 3-methylsulphinyl-propionic acid, S-ethyl3-ethylthiopropionylthioate, S-methyl3-methylthio-2-propylcarboylthioate, 3-mercaptopropionic acid, S-methyl3-methylthioproponothioate, methyl 3-methylthiopropionate, methyl3-mercaptopropionate, 3-methylthiopropionic acid,S-metyl-3-methylsulphinylpropionothioate,S-methyl-3-methylsulphonylpropionothioate or S-methyl3-methoxypropionothioate.
 9. A medicament in unit-dosage form comprisinga composition of claim 13 in the form of a tablet, dragee, capsule,pill, ampoule or suppository.
 10. A method of treating inflammatoryprocesses in warm-blooded animals which comprises administering to thesaid animals an antiphlogistically effective amount of a compound asdefined in claim 1 either alone or in admixture with a diluent or in theform of a medicament.
 11. A method according to claim 10 in which theactive compound is administered in an amount of 0.4 to 16 mg per kg ofbody weight per day.
 12. A method according to claim 11 in which theactive compound is administered in an amount of 2 mg to 10 mg per kgbody weight per day.
 13. A method according to claim 11 or 12 in whichthe active compound is administered parenterally.